Clinical, post-mortem, imaging, and animal biochemical and behavioral studies have all contributed to the evidence that chronic stress and depression produce biochemical, structural, and functional changes in brain regions such as hippocampus and frontal cortex. Clinical and animal behavioral responses to anti-depressant medications are delayed by several days, despite the rapid onset of their pharmacological action on monoamine neurotransmission, suggesting that slower, perhaps transcriptional or structural, adaptations are required for their efficiency. Some of the neuronal changes are reminiscent of the effects of neurotrophic factors on cultured neurons. Prior studies, including our own, have demonstrated that stress down-regulates expression of the neurotrophin, brain-derived neurotrophic factor (BDNF), in hippocampus and other cortical areas. Furthermore we, and others, have shown that antidepressant drugs and electroconvulsive seizures up-regulate BDNF expression. Our hypothesis is that the reduction in neurotrophin mediates, in part, the effects of stress, and that increased BDNF contributes to the effect of antidepressant medications. Furthermore, if BDNF mediates some stress and anti-depressant effects, they would likely be transmitted by one or more of the various intracellular signaling pathway proteins regulated by its receptor, TrkB. Therefore, we also propose that the regulation of these signaling proteins, particularly ERK, mediates biochemical and behavioral effects of stress, neurotrophins, and chemical anti- depressants. We will investigate the nature of this regulation in detail and modulate ERK, as well as the other specific intracellular signaling proteins, assessing biochemical, behavioral, and functional electrophysiological endpoints. Our preliminary results demonstrate that (1) BDNF and NT-3 have in vivo activity in animal models of antidepressant activity, (2) neurotrophin intracellular signaling proteins, particularly ERK, are dynamically regulated by stress and anti- depressants, and (3) deprivation of BDNF or ERK activity has profound effects on serotonergic function in cortical neurons. We will further extend and test the significance of these observations, using behavioral, molecular, and electrophysiological approaches. Studies in this proposed project will provide insight into the biological mechanisms of stress and anti-depressants, and may provide potential new avenues for therapeutic intervention for depression and stress disorders.